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Grant Abstract

Grant Number: 5R21AT001608-02
Project Title: Modulation of Autoimmunity by Green Tea Polyphenols

Abstract: DESCRIPTION (provided by applicant): Many herbs and other plant products in Chinese, Indian, and Nigerian medicine, etc. belonging to the realm of complementary and alternative medicine (CAM) have been found to be beneficial against a variety of diseases and are quite popular with the public; yet, there is skepticism in the medical community about the scientific rationale for the use of these agents. One reason for this skepticism is that many of these plant products have neither been tested in well-controlled experimental systems nor their mechanisms of action have been well defined. Several investigators have reported that the polyphenolic fraction of green tea (Camellia sinensis) (PGT) has anti-cancer and anti- inflammatory properties. PGT contains polyphenolic catechins, which are thought to be responsible for most of the beneficial effects of green tea observed in various studies. Our pilot experiments using the rat adjuvant-induced arthritis (AA) model for human rheumatoid arthritis (RA) have shown that oral feeding of 0.8% (w/v) PGT to Lewis rats for 2 wk before induction of AA affords significant protection from the disease. We now propose to further elaborate on the anti-arthritic activity of PGT, and determine the immunological basis of this effect. AA is inducible in Lewis rats by injection s.c. of heat-killed M. tuberculosis (Mtb). In AA, the 65 kD mycobacterial heat- shock protein (Bhsp65) is the focus of the T cell responses of arthritic Lewis rats. The T cells specific for the determinant (epitope) region 180-188/177-191 of Bhsp65 are pathogenic, whereas those directed against Bhsp65 carboxy-terminal determinants (BCTD) are disease-regulating in nature. This information makes AA an ideal model for testing the immunologic basis of the anti-arthritic activity of PGT. We hypothesize that the protective/beneficial effect of PGT against arthritis (AA) involves differential modulation of the antigen-specific T cell responses to the pathogenic and/or regulatory determinants of Bhsp65. This effect could be achieved by the action of PGT either on the function of the antigen presenting cells (APC) or on the type of cytokines secreted by Bhsp65-specific T cells, e.g., immune deviation from pro-inflammatory T helper 1 (Thl) to anti-inflammatory T helper 2 (Th2) type cytokines, or by facilitating the secretion of immunosuppressive cytokine TGF-b, or both. We plan to determine the effects of PGT- (Aim 1) on the proliferative and cytokine response of T cells against the pathogenic vs. regulatory determinants of Bhsp65, and on the APC by testing both for changes in the surface expression of class n major histocompatibility complex (MHC)/ costimulatory B7 molecules (by flow cytometry) and/or in the efficacy of processing and presentation of Bhsp65 (using epitope-specific T cell lines) during the course of AA; and (Aim 2) on clinical AA by determining whether PGT treatment is additive to, or synergistic with, the beneficial effect of BCTD peptides for the prevention of AA or for treatment of ongoing AA. The results of this study would help in establishing a reliable scientific basis for the use of PGT in autoimmune arthritis, and in developing better therapeutic approaches for RA.

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